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TOWARD A BIOLOGICAL UNDERSTANDING OF THE AGEING PROCESS ROBIN HOLLIDAY* Introduction The majority ofstudies in the field of ageing are descriptive. A variety of experimental procedures have been used to examine changes in the cells, tissues, or organs during the ageing of various animal species. These many empirical observations ofage-related changes are not, however , usually easy to interpret in terms of the underlying mechanisms that may bring about the ageing process. Theories of ageing propose such mechanisms, but for the most part these have been difficult to test directly with appropriate experimental systems, and the significance of the results obtained is often the object of controversy. It has often been stated that there are two major types of ageing theory. One is that ageing is programmed in a temporal sense: there is a clock or pacemaker mechanism that, after a given period of time, initiates the spectrum of changes that cause or accompany the ageing process . Alternatively, this process can be regarded as a running down of the programme for development, which first produces a normal adult capable of reproduction and later leads to the loss of fertility, senescence , and death. The second class of theories is stochastic: ageing is envisaged as a multihit or multistep process owing to the gradual accumulation of innumerable random defects or errors in macromolecules ; the death of individual cells, and accumulated damage to tissues or organs, all of which lead to the loss of homeostasis that is seen in senescent animals. When the genetic control of ageing is considered, the Paper based on the Lord Cohen Medal lecture at the Ageing Well conference, Brighton, September 17, 1987. The author thanks Leslie Orgel and many colleagues, particularly Tom Kirkwood, Zhores Medvedev, Ian Buchanan, and Bob Rosenberger, for their helpful discussions about the nature of the ageing process, and Sarah Moore for her help in preparing the manuscript. *CSIRO Laboratory for Molecular Biology, P.O. Box 184, North Ryde, Sydney, N.S.W. 2113, Australia.© 1988 by The University of Chicago. All rights reserved. 0031-5982/89/3201-0605$01.00 Perspectives in Biology and Medicine, 32, 1 ¦ Autumn 1988 | 109 distinction between programme and stochastic theories to some extent breaks down, and this can be illustrated by a specific example. The teeth of a horse wear down from grazing at an approximately constant rate and, unlike those of the rabbit, are not renewed by growth at the root. The age of a horse can, with reasonable accuracy, be determined by examination of wear on the teeth. Furthermore, excessive wear can lead to loss of function, inability of the animal to graze, and therefore death from starvation. This raises basic questions. Is the length of the tooth and its consequent life span genetically programmed? Does the tooth lose function from wear and tear? Is death of the animal due to an ageing process? The answer to each of these questions must be affirmative and therefore illustrates the difficulty of distinguishing programmes from stochastic events. The example of the horse's teeth is not trivial, and many similar cases of temporal deterioration of body structures could be cited. Design of the Organism There is no reason to believe that organisms necessarily have a finite life span. Most microbial species divide asexually and can grow indefinitely . Plants have complex differentiated tissues, but there are many examples oftheir continual vegetative propagation. Simple animals such as sponges, anemones, and flatworms have considerable powers of renewal and regeneration and, as far as can be judged, do not undergo ageing. The germline cells of all sexually reproducing animals must be potentially immortal, otherwise these species would not survive. Mammalian cells which have undergone malignant transformation are immortalised since populations can be grown indefinitely in culture or by transfer from animal to animal. Williams [1] made the strong argument that, if natural selection can lead to the evolution of the extraordinarily complex process of development from fertilised egg to the adult, then the evolution of indefinite maintenance of the adult seems trivial by comparison. As we shall see, the role of body maintenance and the eventual failure ofmaintenance may well be the key to an understanding of the ageing process. With regard...


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